Tag: serotonin

Serotonin Linked to Somatic Awareness, a Condition Long Thought To Be Imaginary

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An international team spearheaded by researchers at McGill University has discovered a biological mechanism that could explain heightened somatic awareness, a condition where patients experience physical discomforts for which there is no physiological explanation.

Patients with heightened somatic awareness often experience unexplained symptoms – headaches, sore joints, nausea, constipation or itchy skin – that cause emotional distress, and are twice as likely to develop chronic pain. The condition is associated with illnesses such as fibromyalgia, rheumatoid arthritis, and temporomandibular disorders, and is thought to be of psychological origin.

“Think of the fairy tale of the princess and the pea,” says Samar Khoury, a postdoctoral fellow at McGill’s Alan Edwards Centre for Research on Pain. “The princess in the story had extreme sensitivity where she could feel a small pea through a pile of 20 mattresses. This is a good analogy of how someone with heightened somatic awareness might feel; they have discomforts caused by a tiny pea that doctors can’t seem to find or see, but it’s very real.”

Thanks to an existing study on genetic association, Samar Khoury and her colleagues might have found the elusive pea capable of explaining somatic awareness.

Their work, recently published in the Annals of Neurology, used data available through the Orofacial Pain: Prospective Evaluation and Risk Assessment cohort and demonstrates that patients who suffer from somatic symptoms share a common genetic variant. The mutation leads to the malfunctioning of an enzyme critical for the production of serotonin, a neurotransmitter with numerous biological functions.

“I am very happy and proud that our work provides a molecular basis for heightened somatic symptoms,” says Luda Diatchenko, lead author of the new study and a professor in McGill’s Faculty of Dentistry. “We believe that this work is very important to patients because we can now provide a biological explanation of their symptoms. It was often believed that there were psychological or psychiatric problems, that the problem was in that patient’s head, but our work shows that these patients have lower levels of serotonin in their blood.”

The results of their study have laid the groundwork for the development of animal models that could be used to better characterize the molecular pathways in heightened somatic awareness. Above all, Diatchenko and Khoury hope their work will pave the way for treatment options.

“The next step for us would be to see if we are able to target serotonin levels in order to alleviate these symptoms,” says Diatchenko, who holds the Canada Excellence Research Chair in Human Pain Genetics.

This work was supported by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, the National Institutes of Health and the National Institute of Dental and Craniofacial Research.

https://reachmd.com/news/serotonin-linked-to-somatic-awareness-a-condition-long-thought-to-be-imaginary/1628160/?mkt_tok=eyJpIjoiTTJFM05EYzNORFZsTmpZMSIsInQiOiJ6dnNLckNwK0tZSTUwYnlBcmxBZ1dMSGg4ZTlFQ1FUd2xvOVV5bkpRV0hrOXB5aEs4cG95ckRFNDY2aTFCem41MXQxUTk0ZWtuNjdJMkJ5NUNqRTJzVFFKZkE3ZEpMS2xuMGFBZVBnQXM5WFBZVkpRZW1zZzNscmtUTlJIblJYOSJ9

A new map of the brain’s serotonin system

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anewmapofthe
A 3-D rendering of the serotonin system in the left hemisphere of the mouse brain reveals two groups of serotonin neurons in the dorsal raphe that project to either cortical regions (blue) or subcortical regions (green) while rarely crossing into the other’s domain.

As Liqun Luo was writing his introductory textbook on neuroscience in 2012, he found himself in a quandary. He needed to include a section about a vital system in the brain controlled by the chemical messenger serotonin, which has been implicated in everything from mood to movement regulation. But the research was still far from clear on what effect serotonin has on the mammalian brain.

“Scientists were reporting divergent findings,” said Luo, who is the Ann and Bill Swindells Professor in the School of Humanities and Sciences at Stanford University. “Some found that serotonin promotes pleasure. Another group said that it increases anxiety while suppressing locomotion, while others argued the opposite.”

Fast forward six years, and Luo’s team thinks it has reconciled those earlier confounding results. Using neuroanatomical methods that they invented, his group showed that the serotonin system is actually composed of at least two, and likely more, parallel subsystems that work in concert to affect the brain in different, and sometimes opposing, ways. For instance, one subsystem promotes anxiety, whereas the other promotes active coping in the face of challenges.

“The field’s understanding of the serotonin system was like the story of the blind men touching the elephant,” Luo said. “Scientists were discovering distinct functions of serotonin in the brain and attributing them to a monolithic serotonin system, which at least partly accounts for the controversy about what serotonin actually does. This study allows us to see different parts of the elephant at the same time.”

The findings, published online on August 23 in the journal Cell, could have implications for the treatment of depression and anxiety, which involves prescribing drugs such as Prozac that target the serotonin system – so-called SSRIs (selective serotonin reuptake inhibitors). However, these drugs often trigger a host of side effects, some of which are so intolerable that patients stop taking them.

“If we can target the relevant pathways of the serotonin system individually, then we may be able to eliminate the unwanted side effects and treat only the disorder,” said study first author Jing Ren, a postdoctoral fellow in Luo’s lab.

Organized projections of neurons

The Stanford scientists focused on a region of the brainstem known as the dorsal raphe, which contains the largest single concentration in the mammalian brain of neurons that all transmit signals by releasing serotonin (about 9,000).

The nerve fibers, or axons, of these dorsal raphe neurons send out a sprawling network of connections to many critical forebrain areas that carry out a host of functions, including thinking, memory, and the regulation of moods and bodily functions. By injecting viruses that infect serotonin axons in these regions, Ren and her colleagues were able to trace the connections back to their origin neurons in the dorsal raphe.

This allowed them to create a visual map of projections between the dense concentration of serotonin-releasing neurons in the brainstem to the various regions of the forebrain that they influence. The map revealed two distinct groups of serotonin-releasing neurons in the dorsal raphe, which connected to cortical and subcortical regions in the brain.

“Serotonin neurons in the dorsal raphe project to a bunch of places throughout the brain, but those bunches of places are organized,” Luo said. “That wasn’t known before.”

Two parts of the elephant

In a series of behavioral tests, the scientists also showed that serotonin neurons from the two groups can respond differently to stimuli. For example, neurons in both groups fired in response to mice receiving rewards like sips of sugar water but they showed opposite responses to punishments like mild foot shocks.

“We now understand why some scientists thought serotonin neurons are activated by punishment, while others thought it was inhibited by punishment. Both are correct – it just depends on which subtype you’re looking at,” Luo said.

What’s more, the group found that the serotonin neurons themselves were more complex than originally thought. Rather than just transmitting messages with serotonin, the cortical-projecting neurons also released a chemical messenger called glutamate – making them one of the few known examples of neurons in the brain that release two different chemicals.

“It raises the question of whether we should even be calling these serotonin neurons because neurons are named after the neurotransmitters they release,” Ren said.

Taken together, these findings indicate that the brain’s serotonin system is not made up of a homogenous population of neurons but rather many subpopulations acting in concert. Luo’s team has identified two groups, but there could be many others.

In fact, Robert Malenka, a professor and associate chair of psychiatry and behavioral sciences at Stanford’s School of Medicine, and his team recently discovered a group of serotonin neurons in the dorsal raphe that project to the nucleus accumbens, the part of the brain that promotes social behaviors.

“The two groups that we found don’t send axons to the nucleus accumbens, so this is clearly a third group,” Luo said. “We identified two parts of the elephant, but there are more parts to discover.”

https://medicalxpress.com/news/2018-08-brain-serotonin.html

Scientists made a startling discovery about identifying ourselves after dosing people with LSD

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By Rafi Letzter

Scientists in Switzerland dosed test subjects with LSD to investigate how patients with severe mental disorders lose track of where they end and other people begin.

Both LSD and certain mental disorders, most notably schizophrenia, can make it difficult for people to distinguish between themselves and others. And that can impair everyday mental tasks and social interactions, said Katrin Preller, one of the lead authors of the study and a psychologist at the University Hospital of Psychiatry in Zurich. By studying how LSD breaks down people’s senses of self, the researchers aimed to find targets for future experimental drugs to treat schizophrenia.

“Healthy people take having this coherent ‘self’ experience for granted,” Preller told Live Science, “which makes it difficult to explain why it’s so important.”

Depression, she said, also relates to the sense of self. Whereas people with schizophrenia can lose track of themselves entirely, people with depression tend to “ruminate” on themselves, unable to break obsessive, self-oriented patterns of thought.

But this kind of phenomenon is challenging to study, Preller said.

“If you want to investigate self-experience, you have to manipulate it,” Preller said. “And there are very few substances that can actually manipulate sense of self while patients are lying in our MRI scanner.”

One of the substances that can, however, is LSD. And that’s why this experiment happened in Zurich, Preller said. Switzerland is one of the few countries where it’s possible to use LSD on human beings for scientific research. (Doing so is still quite difficult, though, requiring lots of oversight.)

The experiment itself didn’t sound like the most exciting use of the drug for the test subjects, all of whom were physically healthy and did not have schizophrenia or other illnesses After taking the drug, the subjects lay inside MRI machines with video goggles strapped to their faces, trying to make eye contact with a computer-generated avatar. Once they accomplished this, the subjects then tried to look off at another point in space that the avatar was also looking at. This is the kind of social task, Preller said, that’s very difficult if your sense of self has broken down.

Every study subject tried the task three times: once sober, once on LSD, and once after taking both LSD and a substance called ketanserin. This substance blocks LSD from interacting with a particular serotonin receptor in the brain, which researchers call “5-HT2.”

Previous studies on animals had suggested that 5-HT2 played a key role in LSD’s ability to mess with sense of self. The researchers suspected that blocking the receptor in humans might somewhat reduce the effect of LSD.

But it turned out to more than “somewhat” block the effect: There was no difference between the performance of subjects who took ketanserin and the placebo group.

“This was surprising to us, because LSD interacts with a lot of receptors [in the brain], not just 5-HT2,” Preller said.

But LSD’s most dramatic measurable effects entirely abated when subjects first took ketanserin.

That tentatively indicates that 5-HT2 plays an important role in regulating sense of self in the brain, Preller said. The next step, she added, is to work on drugs that target that receptor and see if they might alleviate some of the symptoms of severe psychiatric illnesses that affect the sense of self.

The paper detailing the study’s results was published today (March 19) at The Journal of Neuroscience.

https://www.livescience.com/62059-schizophrenia-lsd-sense-self.html#?utm_source=ls-newsletter&utm_medium=email&utm_campaign=03202018-ls

Case Western Reserve University Scientists generate first microscopic image of full length serotonin receptor

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3D reconstruction of a serotonin receptor generated by cryo-electron microscopy

by Rebecca Pool

Claiming a world first and using cryo-electron microscopy, researchers from Case Western Reserve University School of Medicine, US, have observed full-length serotonin receptors. The proteins are common drug targets, and the new images provide details about molecular binding sites that could lead to more precise drug design. Serotonin receptors, which reside in cell membranes throughout the body, are highly dynamic and difficult to image. In the past, the receptors have been sectioned into pieces to study, but by capturing full-length samples, researchers have revealed how different portions interact.

Dr Sandip Basak from Physiology and Biophysics, and colleagues, describe ‘a finely tuned orchestration of three domain movements’ that allows the receptors to elegantly control passageways across cell membranes. “The serotonin receptor acts as a gateway, or channel, from outside the cell to inside,” he says. “When serotonin binds onto the receptor, the channel switches conformation from closed to open. It eventually twists into a ‘desensitized’ state, where the channel closes but serotonin remains attached,” he adds. “This prevents it from being reactivated.”

For this study, the researchers used a FEI Titan Krios microscope, operating at 300 kV, and equipped with a Gatan K2-Summit direct detector camera, at the National Cryo-Electron Microscopy Facility in Frederick, Maryland.

“Successful design of safer therapeutics [for cancer therapies and gastrointestinal diseases] has slowed because there is currently a limited understanding of the structure of the serotonin receptor itself, and what happens after serotonin binds,” says research leader, Professor Sudha Chakrapani. “Our new structure of the serotonin receptor in the resting state has the potential to serve as a structural blueprint to drive targeted drug design and better therapeutic strategies.”

This research is published in Nature Communications.

https://microscopy-analysis.com/editorials/editorial-listings/first-images-full-length-receptor-structure

How LSD Makes Your Brain One With The Universe

On By A.P.In brain, Drugs, hallucination, hallucinations, LSD, lysergic acid diethylamaide, Psilocybin2 Comments

lsd

by Angus Chen

Some users of LSD say one of the most profound parts of the experience is a deep oneness with the universe. The hallucinogenic drug might be causing this by blurring boundaries in the brain, too.

The sensation that the boundaries between yourself and the world around you are erasing correlates to changes in brain connectivity while on LSD, according to a study published Wednesday in Current Biology. Scientists gave 15 volunteers either a drop of acid or a placebo and slid them into an MRI scanner to monitor brain activity.

After about an hour, when the high begins peaking, the brains of people on acid looked markedly different than those on the placebo. For those on LSD, activity in certain areas of their brain, particularly areas rich in neurons associated with serotonin, ramped up.

Their sensory cortices, which process sensations like sight and touch, became far more connected than usual to the frontal parietal network, which is involved with our sense of self. “The stronger that communication, the stronger the experience of the dissolution [of self],” says Enzo Tagliazucchi, the lead author and a researcher at the Netherlands Institute for Neuroscience.

Tagliazucchi speculates that what’s happening is a confusion of information. Your brain on acid, flooded with signals crisscrossing between these regions, begins muddling the things you see, feel, taste or hear around you with you. This can create the perception that you and, say, the pizza you’re eating are no longer separate entities. You are the pizza and the world beyond the windowsill. You are the church and the tree and the hill.

Albert Hofmann, the discoverer of LSD, described this in his book LSD: My Problem Child. “A portion of the self overflows into the outer world, into objects, which begin to live, to have another, a deeper meaning,” he wrote. He felt the world would be a better place if more people understood this. “What is needed today is a fundamental re-experience of the oneness of all living things.”

The sensation is neurologically similar to synesthesia, Tagliazucchi thinks. “In synesthesia, you mix up sensory modalities. You can feel the color of a sound or smell the sound. This happens in LSD, too,” Tagliazucchi says. “And ego dissolution is a form of synesthesia, but it’s a synesthesia of areas of brain with consciousness of self and the external environment. You lose track of which is which.”

Tagliazucchi and other researchers also measured the volunteers’ brain electrical activity with another device. Our brains normally generate a regular rhythm of electrical activity called the alpha rhythm, which links to our brain’s ability to suppress irrelevant activity. But in a different paper published on Monday in the Proceedings of the National Academy of Sciences, he and several co-authors show that LSD weakens the alpha rhythm. He thinks this weakening could make the hallucinations seem more real.

The idea is intriguing if still somewhat speculative, says Dr. Charles Grob, a psychiatrist at the Harbor-UCLA Medical Center who was not involved with the work. “They may genuinely be on to something. This should really further our understanding of the brain and consciousness.” And, he says, the work highlights hallucinogens’ powerful therapeutic potential.

The altered state of reality that comes with psychedelics might enhance psychotherapy, Grob thinks. “Hallucinogens are a catalyst,” he says. “In well-prepared subjects, you might elicit powerful, altered states of consciousness. [That] has been predicative of positive therapeutic outcomes.”

In recent years, psychedelics have been trickling their way back to psychiatric research. LSD was considered a good candidate for psychiatric treatment until 1966, when it was outlawed and became very difficult to obtain for study. Grob has done work testing the treatment potential of psilocybin, the active compound in hallucinogenic mushrooms.

He imagines a future where psychedelics are commonly used to treat a range of conditions. “[There could] be a peaceful room attractively fixed up with nice paintings, objects to look at, fresh flowers, a chair or recliner for the patient and two therapists in the room,” he muses. “A safe container for that individual as they explore deep inner space, inner terrain.”

Grob believes the right candidate would benefit greatly from LSD or other hallucinogen therapy, though he cautions that bad experiences can still happen for some on the drugs. Those who are at risk for schizophrenia may want to avoid psychedelics, Tagliazucchi says. “There has been evidence saying what could happen is LSD could trigger the disease and turn it into full-fledged schizophrenia,” he says. “There is a lot of debate around this. It’s an open topic.”

Tagliazucchi thinks that this particular ability of psychedelics to evoke a sense of dissolution of self and unity with the external environment has already helped some patients. “Psilocybin has been used to treat anxiety with terminal cancer patients,” he says. “One reason why they felt so good after treatment is the ego dissolution is they become part of something larger: the universe. This led them to a new perspective on their death.”

http://www.npr.org/sections/health-shots/2016/04/13/474071268/how-lsd-makes-your-brain-one-with-the-universe

Medication for Parkinson’s disease shown to lower morality and increase willingness to harm others

On By A.P.In Depression, morality, neurodegeneration, Neurology, Neuropsychiatric Disease, Parkinson's disease, Psychiatry, psychologist, psychology, psychopath, psychopathic personality, psychopathyLeave a comment


Healthy people who are given commonly prescribed mood-altering drugs see significant changes in the degree to which they are willing to tolerate harm against themselves and others, according to a study published Thursday. The research has implications for understanding human morality and decision-making.

A team of scientists from the University College London (UCL) and Oxford University found that healthy people who were given the serotonin-boosting antidepressant citalopram were willing to pay twice as much to prevent harm to themselves or others, compared to those given a placebo. By contrast, those who were given a dose of the dopamine-enhancing Parkinson’s drug levodopa made more selfish decisions, overcoming an existing tendency to prefer harming themselves over others.

The researchers said their findings, published in the journal Current Biology, provided clues to the neurological and chemical roots of common clinical disorders like psychopathy, which causes people to disregard the emotions of others.

The researchers compared how much pain subjects were willing to anonymously inflict on themselves or other people in exchange for money. Out of 175 subjects, 89 were given citalopram or a placebo and 86 were given levodopa or a placebo.

They were anonymously paired up into decision-makers and receivers, and all subjects were given shocks at their pain threshold. The decision-makers were then allowed to choose a different amount of money in exchange for a different amount of shocks, either to themselves or the receivers.

On average, people who were given a placebo were willing to pay about 35p per shock to prevent harm to themselves and 44p per shock to prevent harm to others. Those who were given citalopram became more averse to harm, paying an average of 60p to avoid harm to themselves and 73p per shock to avoid harm to others. This meant that citalopram users, on average, delivered 30 fewer shocks to themselves and 35 fewer shocks to others.

However, those who were given levodopa became more selfish, showing no difference in the amount they were willing to pay to prevent shocks to themselves or others. On average, they were willing to pay about 35p per shock to prevent harm to themselves or others, meaning that they delivered on average about 10 more shocks to others during the trial than those who took a placebo. They also showed less hesitation about shocking others than those given the placebo.

Similar research conducted by the same team in November found that subjects were willing to spare the stranger pain twice as often as they spared themselves, indicating that they preferred harming themselves over others for profit, a behavior known as “hyper-altruism.”

“Our findings have implications for potential lines of treatment for antisocial behavior, as they help us to understand how serotonin and dopamine affect people’s willingness to harm others for personal gain,” Molly Crockett of UCL, the study’s lead author, said in a press release. “We have shown that commonly-prescribed psychiatric drugs influence moral decisions in healthy people, raising important ethical questions about the use of such drugs.

“It is important to stress, however, that these drugs may have different effects in psychiatric patients compared to healthy people. More research is needed to determine whether these drugs affect moral decisions in people who take them for medical reasons.”

http://www.ibtimes.com/antidepressants-affect-morality-decision-making-new-study-finds-1995363

Should psychedelics be declassified in order to examine their therapeutic potential in some forms of mental illness?

On By A.P.In Anxiety, Depression, Drugs, hallucinogen, LSD, lysergic acid diethylamaide, MDMA (Ecstasy), Medicine, Neuropsychiatric Disease, PsychosisLeave a comment

Psychedelics were highly popular hallucinogenic substances used for recreational purposes back in the 1950s and 1960s. They were also widely used for medical research looking into their beneficial impact on several psychiatric disorders, including anxiety and depression. In 1967, however, they were classified as a Class A, Schedule I substance and considered to be among the most dangerous drugs with no recognized clinical importance. The use of psychedelics has since been prohibited.

Psychiatrist and honorary lecturer at the Institute of Psychiatry, Psychology and Neuroscience, at Psychiatrist and honorary lecturer at the Institute of Psychiatry, Psychology and Neuroscience, at King’s College London, James Rucker, MRCPsych, is proposing to reclassify and improve access to psychedelics in order to conduct more research on their therapeutic benefits. He believes in the potential of psychedelics so much that late last month he took to the pages of the prestigious journal the BMJ to make his case. He wrote that psychedelics should instead be considered Schedule II substances which would allow a “comprehensive, evidence based assessment of their therapeutic potential.”

“The Western world is facing an epidemic of mental health problems with few novel therapeutic prospects on the horizon,” Rucker told Psychiatry Advisor, justifying why studying psychedelics for treating psychiatric illnesses is so important.

Rucker recognizes that the illicit substance may be harmful to some people, especially when used in a recreational and uncontrolled context. He cited anecdotal reports of the substance’s disabling symptoms, such as long-term emotionally charged flashbacks. However, he also believes that psychedelic drugs can have positive outcomes in other respects.

“The problem at the moment,” he argued, “is that we don’t know who would benefit and who wouldn’t. The law does a good job of preventing us from finding out.”

From a biological perspective, psychedelics act as an agonist, a substance that combines with a receptor and initiates a physiological response to a subtype of serotonin known as 5HT2a. According to Rucker, this process influences the balance between inhibitory and excitatory neurotransmitters.

“The psychedelics may invoke a temporary state of neural plasticity within the brain, as a result of which the person may experience changes in sensory perception, thought processing and self-awareness,” Rucker speculated. He added that psychedelic drugs can act as a catalyst that stirs up the mind to elicit insights into unwanted cycles of feelings, thoughts and behaviors.

“These cycles can then be faced, expressed, explored, interpreted, accepted and finally integrated back into the person’s psyche with the therapist’s help,” he explained. Reclassifying psychedelics could mean that the mechanism by which these substances can help with anxiety, depression and psychiatric symptoms could be studied and understood better.

Several experts in the field of drug misuse have disagreed strongly with Rucker’s proposals in this area, and are quick to refute his findings and recommendations. Nora Volkow, MD, director of the National Institute on Drug Abuse (NIDA), emphasized the fact that psychedelics can distort a person’s perception of time, motion, colors, sounds and self. “These drugs can disrupt a person’s ability to think and communicate rationally, or even to recognize reality, sometimes resulting in bizarre or dangerous behavior,” she wrote on a NIDA webpage dealing with hallucinogens and dissociative drugs.

“Hallucinogenic drugs are associated with psychotic-like episodes that can occur long after a person has taken the drug,” she added. Volkow also says that, despite being classified as a Schedule I substance, the development of new hallucinogens for recreational purposes remains of particular concern.

Rucker has several suggestions to help mediate the therapeutic action of the drug during medical trials, and thereby sets out to rebut the concerns of experts such as Volkow. When a person is administered a hallucinogen, they experience a changed mental state. During that changed state, Rucker points out, it is possible to control what he describes as a “context,” and thereby make use of the drug more safe.

According to Rucker, the term “context” is divided into the “set” and the “setting” of the drug experience. “By ‘set,’ I mean the mindset of the individual and by ‘setting’ I mean the environment surrounding the individual,” he explained.

To prepare the mindset of the person, Rucker said that a high level of trust between patient and therapist is essential. “A good therapeutic relationship should be established beforehand, and the patient should be prepared for the nature of the psychedelic experience,” he suggested. The ‘setting’ of the drug experience should also be kept closely controlled — safe, comfortable and low in stress.

It is also necessary to screen participants who undergo the drug experience in order to minimize the risk of adverse effects. Rucker suggested screening patients with an established history of severe mental illness, as well as those at high risk of such problems developing. It is also important to screen the medical and drug history of participants.

“The action of psychedelics is changed by many antidepressant and antipsychotic drugs and some medications that are available over the counter, so a full medical assessment prior to their use is essential,” he said.

In order to avoid the danger of addiction, psychedelics should be given at most on a weekly basis. Indeed, for many patients, very few treatments should be required. “The patient may need only one or two sessions to experience lasting benefits, so the course should always be tailored to the individual,” Rucker advised.

If there are any adverse effects during the psychedelic experience, a pharmacological antagonist or antidote to the drug can be administered to immediately terminate the experience. “This underlines the importance of medical supervision being available at all times,” Rucker noted.

Psychedelics are heavily influenced by the environment surrounding the drug experience. Rucker is proposing they be administered under a controlled setting and with a trusted therapist’s supervision. Together with a reclassification of the drug, medical research could generate a better understanding and application of the benefits of psychedelics to mental health.

1.Rucker JJH. Psychedelic drugs should be legally reclassified so that researchers can investigate their therapeutic potential. BMJ. 2015; 350:h2902.

http://www.bmj.com/content/350/bmj.h2902/related